P1025: RUXOLITINIB-ASSOCIATED CRYPTOCOCCOSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: M.-A. Gaman
Journal: HemaSphere (2022)

Background: The use of the JAK 1/2 inhibitor ruxolitinib (RUX) in myeloproliferative neoplasms (MPNs), namely primary (PMF) or secondary myelofibrosis (MF) and polycythemia vera (PV), has been associated with the development of opportunistic infections due to the immunosuppressive actions of this drug on cellular immunity. However, there is still controversy regarding the association between ruxolitinib treatment and the occurrence of cryptococcosis, a fungal infection caused by the yeast Cryptococcus neoformans or Cryptococcus gattii. Aims: To report on cryptococcosis cases in RUX-treated MPNs and report on epidemiology, clinical manifestations, RUX associations, outcomes. Methods: Systematic search computed in PubMed/Medline, Web of Science and SCOPUS, from the inception of these databases until 28.02.2022, to identify relevant English-written articles. Eligibility criteria: 1. Confirmed MPNs diagnosis, 2. Confirmed diagnosis of cryptococcosis, 3. MPNs patients receiving RUX therapy. Results: The systematic search yielded 60 potentially relevant papers. After removal of duplicates (n=20) and screening of abstracts/titles (n=29), 11 manuscripts were selected for full-text review. After applying the eligibility criteria, 10 articles were entered into the qualitative and quantitative analysis. In total, 10 case reports on cryptococcosis occurring in RUX-treated MPNs patients were detected: 80.0% males, mean age 66.8±8.3 years, range 51-79 years. Most reports (70.0%) came from Asia (3 from Japan, 2 from Thailand, 1 from India and Taiwan each) and from the USA (30.0%) and were published between 2013 and 2021. In total, 70% were diagnosed with PMF, whereas cryptococcosis also occurred in PV, post-PV MF or post-ET MF (10.0%, 1 subject each). The average time from RUX initiation was 22.1±14.5 (6-48) months. HIV status was reported in 60.0% of cases and all subjects were apparently immunocompentent and had negative HIV screening. Cryptococcosis was caused by Cryptococcous neoformans only and occurred most commonly as disseminated infection (40.0%), followed by cryptococcal meningitis (30.0%) or pulmonary cryptococcosis (30.0%). Cryptococcosis co-occurred with tuberculosis (20.0%), disseminated histoplasmosis (10.0%) or Mycobacterium haemophilum cellulitis (10.0%). Most common presentations were fever (70.0%), neurological symptoms/signs (headache, consciousness/visual disturbances, 40.0%), shortness of breath (30.0%) or fatigue/lethargy (30.0%). Positive cryptococcosis diagnosis was established based on serum/cerebrospinal fluid (CSF) cryptococcal antigen positivity (80.0%) and/or positive CSF, blood or bronchoalveolar fluid cultures (70.0%). Specific treatment consisted in amphotericin B (50.0%) and/or fluconazole (70.0%). Amphotericin B was given in combination with flucytosine (20.0%) or fluconazole (20.0%) or in monotherapy (30.0%). Other combinations or drugs, i.e., isavuconazole, voriconazole, were used due to renal toxicity related to amphotericin B use. RUX was discontinued in 70.0% of cases and restarted in 20.0% of subjects. Cryptococcosis-related death occurred in 30.0% of cases. Image:Summary/Conclusion: Cryptococcosis can developed during ongoing RUX therapy in MPNs subjects, even if apparently immunocompetent, potentially due to the immunosuppressive actions of this drug on cellular immunity. Screening for Cryptococcus neoformans in selected individuals might reduce the risk of disseminated infection and death. RUX discontinuation during antifungal treatment is advised due to reported progression of lesions and drug-drug interactions with antifungal agents.